title: Multiscale modeling of the causal functional roles of nsSNPs in a genome-wide association study: application to hypoxia.
abstract: BACKGROUND
  It is a great challenge of modern biology to determine the functional roles of non-synonymous Single Nucleotide Polymorphisms (nsSNPs) on complex phenotypes. Statistical and machine learning techniques establish correlations between genotype and phenotype, but may fail to infer the biologically relevant mechanisms. The emerging paradigm of Network-based Association Studies aims to address this problem of statistical analysis. However, a mechanistic understanding of how individual molecular components work together in a system requires knowledge of molecular structures, and their interactions.
  
  
  RESULTS
  To address the challenge of understanding the genetic, molecular, and cellular basis of complex phenotypes, we have, for the first time, developed a structural systems biology approach for genome-wide multiscale modeling of nsSNPs--from the atomic details of molecular interactions to the emergent properties of biological networks. We apply our approach to determine the functional roles of nsSNPs associated with hypoxia tolerance in Drosophila melanogaster. The integrated view of the functional roles of nsSNP at both molecular and network levels allows us to identify driver mutations and their interactions (epistasis) in H, Rad51D, Ulp1, Wnt5, HDAC4, Sol, Dys, GalNAc-T2, and CG33714 genes, all of which are involved in the up-regulation of Notch and Gurken/EGFR signaling pathways. Moreover, we find that a large fraction of the driver mutations are neither located in conserved functional sites, nor responsible for structural stability, but rather regulate protein activity through allosteric transitions, protein-protein interactions, or protein-nucleic acid interactions. This finding should impact future Genome-Wide Association Studies.
  
  
  CONCLUSIONS
  Our studies demonstrate that the consolidation of statistical, structural, and network views of biomolecules and their interactions can provide new insight into the functional role of nsSNPs in Genome-Wide Association Studies, in a way that neither the knowledge of molecular structures nor biological networks alone could achieve. Thus, multiscale modeling of nsSNPs may prove to be a powerful tool for establishing the functional roles of sequence variants in a wide array of applications.
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Xie
authors.forename: Clara
authors.initials: C
authors.lastname: Ng
authors.forename: Thahmina
authors.initials: T
authors.lastname: Ali
authors.forename: Raoul
authors.initials: R
authors.lastname: Valencia
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Ferreira
authors.forename: Vincent
authors.initials: V
authors.lastname: Xue
authors.forename: Maliha
authors.initials: M
authors.lastname: Tanweer
authors.forename: Dan
authors.initials: D
authors.lastname: Zhou
authors.forename: Gabriel G
authors.initials: GG
authors.lastname: Haddad
authors.forename: Philip E
authors.initials: PE
authors.lastname: Bourne
authors.forename: Lei
authors.initials: L
authors.lastname: Xie
mesh_terms: D000220:Adaptation, Biological / Q000235:genetics*; D000494:Allosteric Regulation; D019943:Amino Acid Substitution / Q000235:genetics*; D000693:Anaerobiosis; D000818:Animals; D019295:Computational Biology; D004331:Drosophila melanogaster; D055106:Genome-Wide Association Study / Q000379:methods*; D008957:Models, Genetic; D008958:Models, Molecular; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D060066:Protein Interaction Maps / Q000235:genetics; D011506:Proteins / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D049490:Systems Biology / Q000379:methods
chemical_list: D011506:Proteins